Mitochondrial dysfunction in metabolic diseases

Development of a bioassay to make use of mtDNA signatures as non-invasive biomarkers in the stratification of diabetic patients that can be implemented in personalized medicine protocols.

Summary:

One of the most prevalent age-related diseases is Diabetes mellitus its complications are a major cause of mortality and morbidity, and a massive burden on the health services having a strong negative impact on the healthy aging of millions of European citizens. Classical treatment approaches have focused mainly on the control of glucose levels a focus that has been demonstrated insufficient to prevent or predict the development of complication. Even with the best glucose control the diabetic complications develop, highlighting the need to provide clinicians with new tools that help to implement novel personalized medicine approaches.

Mitochondrial dysfunction has been amply demonstrated to be associated with both the origin and the development of diabetes and its complications. Leading edge scientific and technical developments have just recently made possible to directly evaluate mitochondrial dysfunction in human blood samples and have been used to demonstrate its value as prognostic biomarker in metabolic-related diseases.

Now, we aim to develop a bioassay that can quantitatively evaluate the response to standard anti-diabetic treatments in terms of mitochondrial dysfunction and that can be used in clinical practice through the implementation of personalized medicine protocols to prevent the development of diabetic complications.

To that end, we will make use of two well-established mouse models for type II diabetes and its complications, the db/db mice and PGC-1a-/- mice that show mitochondrial dysfunction in the absence of hyperglicaemia. These animals will be treated with the most common anti-diabetic agents used in clinical practice. Disease development will be evaluated and mitochondrial function and mtDNA will be analyzed in tissues and in blood samples. We will correlate disease load with tissue specific mitochondrial damage with that observed in blood samples, in order to validate the best predictive biomarkers. These findings will be translated to human subjects where mitochondrial activity and mtDNA will be analyzed in blood samples of diabetic patients. We will incorporate into the study patients that initiate into an anti-diabetic treatment (metformin, insulin, DPP-4 inhibitors, SGLT-2 inhibitors) that will be evaluated for development of vascular and bone complications complemented with a biochemical analysis of blood samples.